Hereditary hemochromatosis (HFE) is a genetic disorder that results in an excessive accumulation of iron in the body due to inappropriately high intestinal iron absorption. If it remains untreated, this iron overload disease results in cirrhosis of liver, hepatic carcinoma, congestive heart failure, endocrinopathies and premature death. The Cys 282 Tyr mutation in the HFE protein is the most common defective genetic trait known in humans, more prevalent than cystic fibrosis, phenylketonuria and muscular dystrophy combined. Selected bioactive dietary polyphenols, which are abundantly present in green tea and grape seed, are receiving increasing interest from the scientists and consumers due to their reported health benefits for a variety of disorders. Because selected dietary polyphenolic compounds reportedly have a wide range of effects in vivo and vitro, including metal chelating activity, the regular intake of selected dietary polyphenolic compounds may have important role in preventing iron overload by reducing the utilization of dietary iron. Our goals of this application are to examine effects of green tea and grape seed extract (GSE) on intestinal iron absorption and how these bioactive polyphenols affect iron metabolism to provide the groundwork necessary to develop green tea, GSE and their related polyphenolic products as a novel treatment for the human iron overload disorders. Green tea and GSE are chosen as test bioactive dietary polyphenols due to our preliminary data and published literature information. More importantly, they contain low levels of enhancing factors (e.g., ascorbic acid) of iron absorption. Studies showed that green tea and its major polyphenolic compounds EGCG and GSE decrease intestinal iron absorption. Based on this key information, the major goals of this application are to investigate their therapeutic potential using animal models of human iron overload disorders and explore the mechanism by which these polyphenols affect iron status. To address these issues, we will carry out the following Specific Aims: (1) To test the hypothesis that regular consumption of green tea and GSE prevents iron overload, and to evaluate their inhibitory action against different iron absorptive signals in mouse models of human iron overload disease hereditary hemochromatosis. (2) To explore the mechanism by which green tea and GSE inhibit intestinal iron absorption and decrease iron status in various mouse models of human iron overload disease. Since these selected bioactive polyphenols can directly inhibit intestinal iron absorption, successful completion of our studies will help propose future human studies to determine the therapeutic benefits of green tea, GSE and their related polyphenolic compounds in iron overload disorders. Our preliminary data and previously published literature information show the feasibility of this project. A better understanding of the mechanisms of polyphenols'inhibitory action on iron absorption will be important for designing therapeutic strategies that target iron overload disorders.